1887

Abstract

Epstein—Barr virus (EBV) initiates infection of normal B lymphocytes by binding to CD21, a complement receptor. Since EBV, unlike most viruses, preferentially infects resting (non-activated) cells, the present studies were undertaken to evaluate the hypothesis that intracellular signalling pathway(s) triggered by EBV binding to CD21 activate the expression of certain cellular genes, as well as the initially expressed viral genes, and thus enable EBV to infect resting B cells. Experiments with non-transforming EBV, recombinant virus ligand and anti-CD21 MAbs show that EBV binding to CD21 on resting B cells increases CD23 mRNA levels independently of viral gene expression. A panel of five protein kinase C (PKC) and tyrosine kinase (PTK) inhibitors, all with different modes of action, exhibited a distinctive pattern of effects on the EBV induced induction of CD23 expression, ranging from nearly complete inhibition to no influence. The results suggest that distinct PKC isoforms and PTKs are involved in the signalling pathway(s) triggered by EBV binding to CD21. Significantly, the five inhibitors showed the same pattern of effects on the earliest stages of infection (EBNA-2 transcription) and B cell transformation (mitogenesis and colony formation). The identical pattern of effects of these PKC and PTK inhibitors with diverse mechanisms of action on the EBV induced increase in both CD23 and EBNA-2 mRNA levels strongly suggests that their transcription is mediated by an intracellular signalling pathway which shares, at least in part, common members.

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1996-12-01
2022-01-16
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References

  1. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. 1987; Genistein, a specific inhibitor of tyrosine-specific protein kinases. Journal of Biological Chemistry 262:5592–5595
    [Google Scholar]
  2. Aquino A., Lisi A., Pozzi D., Ravagnan G., Grimaldi S. 1993; EBV membrane receptor (CR2) is phosphorylated by protein kinase C (PKC) in the early stages of virus entry into lymphoblastoid cells line (Raji). Biochemical and Biophysical Research Communications 196:794–802
    [Google Scholar]
  3. Aubry J. P., Pochon S., Graber P., Jansen K. U., Bonnefoy J. Y. 1992; CD21 is a ligand for CD23 and regulates IgE production. Nature 358:505–507
    [Google Scholar]
  4. Bohnsack J. F., Cooper N. R. 1988; CR2 ligands modulate human B cell activation. Journal of Immunology 141:2569–2576
    [Google Scholar]
  5. Carter R. H., Tuveson D. A., Park D. J., Rhee S. G., Fearon D. T. 1991; The CD19 complex of B lymphocytes: activation of phospholipase C by a protein tyrosine kinase-dependent pathway that can be enhanced by the membrane IgM complex. Journal of Immunology 147:3663–3671
    [Google Scholar]
  6. Cheung R. K., Dosch H.-M. 1991; The tyrosine kinase Ick is critically involved in the growth transformation of human B lymphocytes. Journal of Biological Chemistry 266:8667–8670
    [Google Scholar]
  7. Chomczynski P., Sacchi N. 1987; Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry 162:156–159
    [Google Scholar]
  8. Cooper N. R. 1994; Interactions of the complement system with microorganisms. In New Aspects of Complement Structure and Function pp 133–149 Edited by Erdei A. Austin: R. G. Landes Co;
    [Google Scholar]
  9. Dosch H. M., Lam P., Hui M. F., Hibi T., Cheung R. K. 1990; EBV utilizes a unique activation pathway for the transformation of human B cells. International Immunology 2:833–848
    [Google Scholar]
  10. Dugas B., Delfraissy J.-F., Calenda A., Peuchmaur M., Wallon C., Rannou M.-T., Galanaud P. 1988; Activation and infection of B cells by Epstein-Barr virus. Journal of Immunology 141:4344–4351
    [Google Scholar]
  11. Fearon D. T., Carter R. H. 1995; The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annual Review of Immunology 13:127–149
    [Google Scholar]
  12. Fukazawa H., Li P. M., Yamamoto C., Murakami Y., Mizuno S., Uehara Y. 1991; Specific inhibition of cytoplasmic protein tyrosine kinases by herbimycin A in vitro. Biochemical Pharmacology 42:1661–1671
    [Google Scholar]
  13. Gazit A., Yaish P., Gilon C., Levitzki A. 1989; Tyrphostins. I. Synthesis and biological activity of protein tyrosine kinase inhibitors. Journal of Medical Chemistry 32:2344–2352
    [Google Scholar]
  14. Gold M. R., DeFranco A. L. 1994; Biochemistry of B lymphocyte activation. Advances in Immunology 55:221–295
    [Google Scholar]
  15. Gopalakrishna R., Chen Z. H., Gundimeda U. 1992; Irreversible oxidative inactivation of protein kinase C by photosensitive inhibitor calphostin C. FEBS Letters 314:149–154
    [Google Scholar]
  16. Gordge P. C., Ryves W. J. 1994; Inhibitors of protein kinase C. Cellular Signalling 6:871–879
    [Google Scholar]
  17. Gordon J., Walker L., Guy G., Brown G., Rowe M., Rickinson A. 1986; Control of human B–lymphocyte replication. II. Transforming Epstein-Barr virus exploits three distinct viral signals to undermine three separate control points in B-cell growth. Immunology 58:591–595
    [Google Scholar]
  18. Guy G. R., Gordon J. 1989; Epstein-Barr virus and a tumour-promoting phorbol ester use similar mechanisms in the stimulation of human B-cell proliferation. International Journal of Cancer 43:703–708
    [Google Scholar]
  19. Hatzfeld A., Fischer E., Levesque J. P., Perrin R., Hatzfeld J., Kazatchkine M. D. 1988; Binding of C3 and C3dg to the CR2 complement receptor induces growth of an Epstein-Barr virus positive human B cell line. Journal of Immunology 140:170–175
    [Google Scholar]
  20. Hurley E. A., Thorley-Lawson D. A. 1988; B cell activation and the establishment of Epstein–Barr virus latency. Journal of Experimental Medicine 168:2059–2075
    [Google Scholar]
  21. Iwasaki T., Uehara Y., Graves L., Rachie N., Bomsztyk K. 1992; Herbimycin A blocks IL-l-induced nf-κ b DNA-binding activity in lymphoid cell lines. FEBS Letters 298:240–244
    [Google Scholar]
  22. Kobayashi E., Nakano H., Morimoto M., Tamaoki T. 1989; Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochemical and Biophysical Research Communications 159:548–553
    [Google Scholar]
  23. Liebowitz D., Kieff E. 1993; Epstein–Barr Virus. In The Human Herpesviruses pp 107–172 Edited by Roizman B., Whitley R. J., Lopez C. New York: Raven Press;
    [Google Scholar]
  24. Liu Y.-J., Cairns J. A., Holder M. J., Abbot S. D., Jansen K. U., Bonnefoy J.-Y., Gordon J., MacLennan C. M. 1991; Recombinant 25kDa CD23 and interleukin 1 alpha promote the survival of germinal centre B cells: evidence for bifurcation in the development of centrocytes rescued from apoptosis. European Journal of Immunology 21:1107–1114
    [Google Scholar]
  25. Luxembourg A. T., Cooper N. R. 1994a; T cell dependent B cell activating properties of antibody-coated small latex beads: a new model for B cell activation. Journal of Immunology 153:604–614
    [Google Scholar]
  26. Luxembourg A. T., Cooper N. R. 1994b; Modulation of signalling via the B cell antigen receptor by CD21, the receptor for C3dg and Epstein-Barr virus. Journal of Immunology 153:4448–4457
    [Google Scholar]
  27. Melchers F., Erdei A., Schulz T., Dierich M. P. 1985; Growth control of activated, synchronized murine B cells by the C3d fragment of human complement. Nature 317:264–267
    [Google Scholar]
  28. Misichak H., Kolch W., Goodnight J., Davidson W. F., Rapp U., Rose John S., Mushinski J. F. 1991; Expression of protein kinase C genes in hemopoietic cells is cell-type and B cell-differentiation stage specific. Journal of Immunology 147:3981–3987
    [Google Scholar]
  29. Nakanishi H., Exton J. H. 1992; Purification and characterization of the zeta isoform of protein kinase C from bovine kidney. Journal of Biological Chemistry 267:16347–16354
    [Google Scholar]
  30. Nemerow G. R., Cooper N. R. 1981; Isolation of Epstein–Barr virus and studies of its neutralization by human IgG and complement. Journal of Immunology 127:272–278
    [Google Scholar]
  31. Nemerow G. R., Cooper N. R. 1984a; Infection of B lymphocytes by a human herpesvirus, Epstein–Barr virus, is blocked by calmodulin antagonists. Proceedings of the National Academy of Sciences, USA 81:4955–4959
    [Google Scholar]
  32. Nemerow G. R., Cooper N. R. 1984b; Early events in the infection of human B lymphocytes by Epstein-Barr virus: the internalization process. Virology 132:186–198
    [Google Scholar]
  33. Nemerow G. R., Wolfert R., McNaughton M. E., Cooper N. R. 1985; Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor. Journal of Virology 55:347–351
    [Google Scholar]
  34. Nemerow G. R., Houghten R. A., Moore M. D., Cooper N. R. 1989; Identification of the epitope in the major envelope protein of Epstein–Barr virus that mediates viral binding to the B lymphocyte EBV receptor (CR2). Cell 56:369–377
    [Google Scholar]
  35. Nemerow G. R., Luxembourg A. T., Cooper N. R. 1994; CD21/ CR2, its role in EBV infection and immune function. Epstein Barr Reports 59–64
    [Google Scholar]
  36. Okabe M., Uehara M. 1993; New insight into oncoprotein-targeted antitumor effect: herbimycin A as an antagonist of protein tyrosine kinase against Pfd–positive leukemia cells. Leukemia and Lymphoma 12:41–49
    [Google Scholar]
  37. Oudinet J. P., Feliers D., Pavlovic-Hournac M. 1992; Immunological identification of protein kinase C-α and protein kinase C-δ in cultured rat mesangial cells: differential sensitivity of the two isoforms towards the protein kinase inhibitor H7. Cellular Signalling 4:559–569
    [Google Scholar]
  38. Rochford R., Hobbs M. V., Gamier J. L., Cooper N. R., Cannon M. J. 1993; Plasmacytoid differentiation of Epstein-Barr virus-transformed B cells in vivo is associated with reduced expression of viral latent genes. Proceedings of the National Academy of Sciences, USA 90:352–356
    [Google Scholar]
  39. Simpson J., Johnson M. S., Mitchell R. 1993; H7-resistant protein kinase C substrates in two-dimensional gels of proestrous rat anterior pituitary gland. Biochimica et Biophysica Acta 1220:69–75
    [Google Scholar]
  40. Sinclair A. J., Farrell P. J. 1995; Host cell requirements for efficient infection of quiescent primary B lymphocytes by Epstein-Barr virus. Journal of Virology 69:5461–5468
    [Google Scholar]
  41. Sinclair A. J., Palmero I., Peters G., Farrell P. J. 1994; EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO Journal 13:3321–3328
    [Google Scholar]
  42. Takahashi I., Kobayashi E., Nakano H., Murakata C., Saitoh H., Suzuki K., Tamaoki T. 1990; Potent selective inhibition of 7-O- methyl UCN-01 against protein kinase C. Journal of Pharmacology and Experimental Therapeutics 255:1218–1221
    [Google Scholar]
  43. Tanner J., Weis J., Fearon D., Whang Y., Kieff E. 1987; Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping and endocytosis. Cell 50:203–213
    [Google Scholar]
  44. Tanner J., Whang Y., Sample J., Sears A., Kieff E. 1988; Soluble gp350/220 and deletion mutant glycoproteins block Epstein–Barr virus adsorption to lymphocytes. Journal of Virology 62:4452–4464
    [Google Scholar]
  45. Tanner J. E., Alfieri C., Chatila T. A., Diaz-Mitoma F. 1996; Induction of interleukin-6 after stimulation of human B-cell CD21 by Epstein-Barr virus glycoproteins gp350 and gp220. Journal of Virology 70:570–575
    [Google Scholar]
  46. Thorley-Lawson D. A., Mann K. P. 1985; Early events in Epstein-Barr virus infection provide a model for B cell activation. Journal of Experimental Medicine 162:45–59
    [Google Scholar]
  47. Thorley-Lawson D. A., Nadler L. M., Bhan A. K., Schooley R. T. 1985; Blast-2 [EBVCS], an early cell surface marker of human B cell activation, is superinduced by Epstein-Barr virus. Journal of Immunology 134:3007–3012
    [Google Scholar]
  48. Uckun F. M., Burkhardt A. L., Jarvis L., Jun X., Stealey B., Dibirdik I., Myers D. E., Tuel-Ahlgren L., Bolen J. B. 1993; Signal transduction through the CD19 receptor during discrete development stages of human B-cell ontogeny. Journal of Biological Chemistry 268:21172–21184
    [Google Scholar]
  49. Uckun F. M., Evans W. E., Forsyth C. J., Waddick K. G., Ahlgren L. T., Chelstrom L. M., Burkhardt A., Bolen J., Myers D. E. 1995; Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science 267:886–891
    [Google Scholar]
  50. Wang F., Gregory C., Sample C., Rowe M., Liebowitz D., Murray R., Rickinson A., Kieff E. 1990; Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. Journal of Virology 64:2309–2318
    [Google Scholar]
  51. Wang F., Kikutani H., Tsang S. –F., Kishimoto T., Kieff E. 1991; Epstein–Barr virus nuclear protein 2 transactivates a ris-acting CD23 DNA element. Journal of Virology 65:4101–4106
    [Google Scholar]
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